The key challenge addressed in this proposal is to develop a means to harness the power of molecular biology to define therapeutic targets for brain disease. This treatment-oriented approach combines the urgency of a practicing neurologist with the knowledge and technology modern science brings to neuroscience. From the basic science perspective, understanding the fundamental root mechanism of disease is an uncompromising goal. From the neurologist's perspective, the perfect cannot be the enemy of the good, leading to five basic points: Success to date in the treatment of brain disease offers a key lesson in focus. Treatments target accessible molecules, and this will dictate how we focus big data analysis. Human neurologic disease is complicated. The best model system for understanding neurologic disorders is the human; studies of human brain material must be integral to developing new treatments. Regardless of the cause of brain disease?and current neuroscience is appropriately focused on tracing ?genetic? (DNA) etiologies?the manifestations of such defects are mediated by the stoichiometry, distribution and variability of cell-specific RNA regulation and its consequent effects on proteins within affected cells. Different cell types contribute to different brain disorders, but the difference between individual cells of any one type is unknown. The differences between them are manifest at the level of RNA, not DNA. The quantity, quality (isoforms) and distribution of targets (e.g., receptors) are enormous. The unique spectrum of diversity of an individual cell type?neurons, astrocytes or microglial cells?is unknown, more so when comparing diseased and normal brain. Using a variety of new strategies, we will study RNA regulation in individual cell types. Bridging these points together requires new methods and computational approaches. The net result of contrasting RNA regulation in individual human cell types in health and disease will uncover otherwise hidden cell type-specific targets for therapeutics.